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3 results on '"Rezart Zhubi"'

1. Comparative structural analyses of the NHL domains from the human E3 ligase TRIM–NHL family

Author

Apirat Chaikuad, Rezart Zhubi, Claudia Tredup, and Stefan Knapp

Subjects
trim nhls, nhl domains, trim e3 ligases, protein interaction domains, β-propeller protein modules, genetic mutations, Crystallography, QD901-999
Abstract

Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of the RING-type E3 ubiquitin ligases that play a role in diverse processes from homeostasis and immune response to viral restriction. While TRIM proteins typically harbor an N-terminal RING finger, a B-box and a coiled-coil domain, a high degree of diversity lies in their C termini that contain diverse protein interaction modules, most of which, both structures and their roles in intermolecular interactions, remain unknown. Here, high-resolution crystal structures of the NHL domains of three of the four human TRIM–NHL proteins, namely TRIM2, TRIM3 and TRIM71, are presented. Comparative structural analyses revealed that, despite sharing an evolutionarily conserved six-bladed β-propeller architecture, the low sequence identities resulted in distinct properties of these interaction domains at their putative binding sites for macromolecules. Interestingly, residues lining the binding cavities represent a hotspot for genetic mutations linked to several diseases. Thus, high sequence diversity within the conserved NHL domains might be essential for differentiating binding partners among TRIM–NHL proteins.

Published
2022
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2. Fragment-based discovery of orphan nuclear receptor Nur77/NGFI-B ligands

Author

Silvia Arifi, Daniel Zaienne, Jan Heering, Thomas Wein, Rezart Zhubi, Apirat Chaikuad, Stefan Knapp, Julian A. Marschner, Daniel Merk, and Publica

Subjects
Virtual screening, Receptors, Steroid, Organic Chemistry, Apoptosis, NR4A, Ligands, Orphan Nuclear Receptors, Biochemistry, Neoplasms, Drug Discovery, Nuclear Receptor Subfamily 4, Group A, Member 1, Humans, Neurodegeneration, Transcription factor, Molecular Biology, Cancer
Abstract

The transcription factor nerve growth factor-induced clone B (NGFI-B, Nur77, NR4A1) is an orphan nuclear receptor playing a role in cell survival and apoptosis regulation. Pharmacological Nur77 modulation holds promise for cancer and (neuro-)inflammatory disease treatment. The available Nur77 ligand scaffolds based on highly lipophilic natural products cytosporone B, celastrol and isoalantolactone are inadequate for the development of potent Nur77 modulators with favorable properties as chemical tools and future drugs. By fragment library screening and subsequent modeling for fragment extension, we have obtained a set of new Nur77 ligands offering alternative chemotypes for the development of Nur77 agonists and inverse agonists. Computer-aided fragment extension in a second stage screening yielded a Nur77 agonist with significant activation efficacy and preference over the related NR4A receptors.

Published
2022

3. Kinase Domain Autophosphorylation Rewires the Activity and Substrate Specificity of CK1 Enzymes

Author

Sierra N. Cullati, Apirat Chaikuad, Jun-Song Chen, Jakob Gebel, Laura Tesmer, Rezart Zhubi, Jose Navarrete-Perea, Rodrigo X. Guillen, Steven P. Gygi, Gerhard Hummer, Volker Dötsch, Stefan Knapp, and Kathleen L. Gould

Subjects
Threonine, Cell Biology, Saccharomyces cerevisiae, Protein Serine-Threonine Kinases, Biochemistry, Article, Substrate Specificity, Casein Kinase Idelta, Genetics, Humans, Phosphorylation, Molecular Biology, Signal Transduction, Biotechnology
Abstract

CK1s are acidophilic serine/threonine kinases with multiple critical cellular functions; their misregulation contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Here, we describe an evolutionarily conserved mechanism of CK1 activity: autophosphorylation of a threonine (T220 in human CK1δ) located at the N-terminus of helix αG, proximal to the substrate binding cleft. Crystal structures and molecular dynamics simulations uncovered inherent plasticity in αG that increased upon T220 autophosphorylation. The phosphorylation-induced structural changes significantly altered the conformation of the substrate binding cleft, affecting substrate specificity. In T220 phosphorylated yeast and human CK1s, activity toward many substrates was decreased, but we also identified a high-affinity substrate that was phosphorylated more rapidly, and quantitative phosphoproteomics revealed that disrupting T220 autophosphorylation rewired CK1 signaling in Schizosaccharomyces pombe. T220 is present exclusively in the CK1 family, thus its autophosphorylation may have evolved as a unique regulatory mechanism for this important family.

Published
2022
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